Although most of the major genes of the nitrogen control system have been identified, cloned, and sequenced, neither the identity of the metabolic signal nor the mechanism of signal transduction has been elucidated. This work is primarily concerned with (a) identifying the metabolic initiator of the regulatory process and (b) defining the function of the PII protein in the regulation of synthesis of glutamine synthetase (GS). Previous studies indicated that an increased serine synthesis is associated with the ability of some D-amino acids to elicit an increased synthesis of GS in the presence of excess ammonium nitrogen. It was also observed that strains carrying mutations in glyA, the gene for serine hydroxymethyltransferase, are deficient in response to the D-amino acids. Subsequent studies with inhibitors and mutants suggest an involvement of the threonine utilization (TUT) cycle, including induction of the glycine cleavage system. However, the distribution of the amino nitrogen from D-glutamate, D-lysine, or D-threonine into serine is not as yet understood. Studies with strains devoid of PII protein show that the absence of PII protein does not lead to an elevation in the level of GS. Therefore, it is not likely that PII has a repressor function. However. it appears that PII is required for the increased synthesis of GS during growth on "derepressing" medium or upon addition of the effector D-amino acids.